Osmotic system for delivery of fluid-sensitive somatotropins to bovine animals

ABSTRACT

A delivery system is disclosed for delivering a fluid-sensitive beneficial agent such as a somatotropin, or an analogue or derivative thereof, to an animal such as a bovine. The delivery system comprises a wall that surrounds an internal compartment, said wall comprising a first wall section that limits the passage of fluid into the system and a second wall section that permits the passage of fluid into the system. The wall may further comprise an end cap which may be adapted for ultrasonic welding to the first wall section and may maintain the beneficial agent in contact with an exit. The compartment comprises a beneficial agent and an expandable driving member. The delivery system comprises an exit for delivering the beneficial agent to the animal. The exit may compensate for slight variations in the efflux rate of the beneficial agent and maintain a sufficient velocity or efflux rate of beneficial agent outward from the device while minimizing diffusion of fluids from the external environment back into the device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/269,596,filed Jul. 1, 1994, now U.S. Pat. No. 5,728,088, which is acontinuation-in-part of application Ser. No. 07/513,361 filed Apr. 20,1990, abandoned, which is a divisional of application Ser. No.07/283,359 filed Dec. 13, 1998 now U.S. Pat. No. 5,034,229.

This application is also related to U.S. Ser. No. 07/512,301, filed Apr.20, 1990, now U.S. Pat. No. 5,174,999; Ser. No. 07/513,327, filed Apr.20, 1990, now U.S. Pat. No. 5,057,318; Ser. No. 513,328, filed Apr. 20,1990, now U.S. Pat. No. 5,037,420; Ser. No. 07/513,330, filed Apr. 20,1990, now U.S. Pat. No. 5,110,596; Ser. No. 07/513,363, filed Apr. 20,1990, now U.S. Pat. No. 5,135,523; and Ser. No. 07/513,528, filed Apr.23, 1990, now U.S. Pat. No. 5,059,423; all of which are divisions ofU.S. Ser. No. 08/283,359 (above); Ser. No. 07/681,848, filed Apr. 8,1991, now abandoned, which is a continuation of U.S. Ser. No. 07/513,328(above); Ser. No. 07/789,241, filed Nov. 7, 1991, now U.S. Pat. No.5,320,616, which is a continuation of U.S. Ser. No. 07/513,369, filedApr. 20, 1990, now abandoned; and Ser. No. 08/203,967, filed Mar. 1,1994, now U.S. Pat. No. 5,630,808, which is a continuation of Ser. No.789,241 (above).

All of the above applications are assigned to ALZA Corporation, PaloAlto, Calif.

FIELD OF THE INVENTION

This invention pertains to both a novel and to an unobvious deliverysystem. Particularly, the invention relates to a delivery system thatoperates by osmosis and more particularly, the invention relates to adevice that protects and administers a fluid-sensitive beneficial agentto a fluid environment.

BACKGROUND OF THE INVENTION

Delivery systems for administering a beneficial agent to a biological,fluid environment of use are known to the prior art. See, for example,U.S. Pat. No. 3,845,770; U.S. Pat. Nos. 3,916,899; 3,995,632; 4,111,202;4,111,203; 4,203,439; 4,327,725; and 4,612,008.

The delivery devices described in the above patents operate successfullyfor their intended use and they can deliver many beneficial agents fortheir intended effects. Now, it has been observed that their use can belimited because they lack the necessary elements to deliver beneficialagents that are sensitive to fluids and to fluids containing biologicalgases. Their use may be limited because beneficial agents that aresensitive to such aqueous-biological fluids or to other fluids externalto the delivery device may be adversely affected by fluids that enterthe device and contact the beneficial agents during operation of thedevice. Examples of such fluid-sensitive agents include proteins,peptides, and hormones. Moreover, the prior art devices lack thenecessary means for their use as implant devices for dispensing suchsensitive agents to a biological fluid-rich environment of use.

It will be appreciated by those versed in the dispensing arts that if adelivery system is provided for administering at a controlled rate andfor protecting a beneficial agent that is sensitive to aqueous andbiological fluids, and which delivery system possesses the kineticability to deliver the protected beneficial agent in effective amountsover time, such a delivery system would have a positive value andrepresent an advancement in the dispensing arts. Likewise, it will beself-evident to those versed in the implant art that a pressing needexists for an implant that is essentially free of the tribulationassociated with the prior art and that, if such an implantable deliverysystem is provided, it would have a practical application in the fieldsof human and veterinary medicine and in the breeding and management offarm animals.

SUMMARY OF THE INVENTION

The present invention is directed to a fluid-imbibing delivery device ordispenser for storing and protecting a fluid-sensitive beneficial agentand for dispensing the beneficial agent to a fluid environment of usefor a prolonged period of time. The device comprises a housing enclosingan internal compartment, the housing having a first wall section and asecond wall section and, optionally, an end cap, the first wall sectionsubstantially restricting the passage of fluid into the delivery device,i.e. it is substantially fluid-impermeable, and the second wall sectionpermitting the passage of fluid into the delivery device, i.e. it isfluid-permeable, in at least a portion. The device further comprises abeneficial agent in that portion of the internal compartment defined bythe first wall section, expandable means for pushing the beneficialagent from the delivery device in that portion of the internalcompartment defined by the second wall section, exit means in the firstwall section or in the end cap, if an end cap is present, and,optionally, a partition layer, including a cantilevered piston member,between the beneficial agent and the expandable means, the partitionlayer being substantially impermeable to fluid. The exit means mayinclude means for maintaining sufficient efflux or outward velocity ofthe beneficial agent from that portion defined first wall section. Thedevice further optionally comprises forming the portion containing thebeneficial agent of a material that reduces the adherence of thebeneficial agent thereto. The device further optionally comprises abuttress to strengthen the joint between the first and second wallsections while smoothing the transition between the same.

One class of fluid-sensitive agents that are presently preferred fordelivery from the devices of the present invention are growth factors,including bovine somatotropin and analogues and derivatives thereof. Thedevices of the present invention provide a means for delivering aneffective amount of a beneficial agent for causing increasedproductivity, such as, in the case of the somatotropins, a higher feedconversion efficiency, improved carcass quality, higher than normal rateof animal weight gain, and increased milk production.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a cross-sectional view of one embodiment of the deliverydevice of the invention, illustrating one structural embodiment of thedelivery system comprising a first walled section and a second walledsection.

FIG. 2 is an enlarged fragmented cross-sectional view of the mating endcap of FIG. 1.

FIG. 3 is an enlarged fragmented cross-sectional view of the tenon andmortise embodiment of the mating end cap of FIG. 2.

FIG. 4 is an enlarged fragmented cross-sectional view of the extendingportion of the mating end cap and first wall section of FIG. 1 whichmaintains the exit passageway in contact with the beneficial agent.

FIG. 5 is an enlarged fragmented cross-sectional view of the jointbetween the first and second wall sections of FIG. 1;

FIG. 6 is an enlarged cross-sectional view of the piston member of FIG.1.

FIG. 7 is an enlarged top elevational view of the piston member of FIG.1.

FIG. 8 is a graph showing the passage of water by the piston of FIG. 1from the internal compartment surrounded by an impermeable first wallsection into the internal compartment surrounded by permeable secondwall section of FIG. 1.

FIG. 9 is a graph showing the passage of water by the piston of FIG. 1from the internal compartment surrounded by an impermeable first wallsection into the internal compartment surrounded by permeable secondwall section of FIG. 1, excluding data ≧three standard deviations fromthe mean

FIG. 10 is a graph showing the pressure requirement for seal releaseover time (hours).

FIG. 11 is a graph showing the effect of exit aperture diameter on waterdiffusion.

DETAILED DESCRIPTION OF THE INVENTION

In the following discussion, like reference numerals refer to likeelements in the figures.

FIG. 1 depicts in opened view one embodiment of the delivery deviceaccording to the present invention. Delivery system 10 of FIG. 1comprises a housing 11 formed of a wall 12, which wall 12 comprises afirst wall section 12a and a second wall section 12b. Wall 12,comprising first wall section 12a and second wall section 12b, surroundsand defines an internal compartment 18. Delivery system 10 has at leastone exit passageway 13 for delivering a beneficial agent 7 formulationfrom delivery system 10. Optionally, the exit passageway can be occludedwith a material like that in seal 30, discussed below, that getsdischarged, leaches or erodes during the time of use. In FIG. 1,delivery system 10 comprises a dome-shaped rear end 8 and a flattenedlead end 9. In embodiments not shown, delivery system 10 can bemanufactured with a pair of rounded or flat ends 8 and 9. The term "leadend", as used herein, generally denotes the end from which beneficialagent 7 is released from the system. In use, either the lead end or therear end may be implanted first.

Wall section 12a may be in the form of a tubular member having a firstand a second open ends 32 and 34, respectively. In this particularembodiment, an enclosure means 36 is positioned on first wall section12a at its end lead 9. In this particular embodiment, the enclosuremeans is in the form of an end cap 38. The wall section 12a and end cap38 together form passageway 13, seal 30 and surround that portion ofinternal compartment 18 that contains a beneficial agent 7 formulation.

Referring now to FIG. 1, wall section 12b has a first or open end 40 anda second or enclosed end 42, the enclosed end at end 8 and the open enddistant therefrom. Open end 40 defines and forms receiving means 19.Receiving means 19, having a first buttress 44 and second buttress 46,is received within enclosing means 20 of first wall section 12a. Firstbuttress 44 can be formed by providing the enclosing means 20 of thefirst wall section 12a with a first interior surface portion 48 having afirst inner or bore diameter and a second interior surface portion 50having a second inner or bore diameter, so that the internal buttress orinterior annular ledge 44 is formed or defined where the first andsecond interior surface portions of wall section 12a meet.

Formed on the outer surface 52 of the wall section 12b is the secondbuttress 46. Second buttress 46 is positioned to abut with the secondopen end 34 of the first wall section 12a when the enclosing means 20 ofthe wall section 12a abuts with the first buttress 44. As a result, thesecond buttress 46 in combination with the first buttress 44 forms adouble butt joint to mate the wall sections 12a and 12b for a strongjoint while minimizing the external discontinuities or surface frictionof the implant device and providing a smooth transition between thefirst and second wall sections. In this particular embodiment, theportion of the second wall section 12b inserted within the first wallsection 12a has the same thickness as that portion outside the firstwall section. In addition, as a result of this construction, the insidesurface of the first and second wall sections facilitates the travel ofthe piston along the formed smooth continuous interior surface.

As best shown in FIG. 5, the buttress 46 includes a buttress engagingsurface 54 for abutting with the first wall section 12a and an exterioror contoured surface 56 to smooth the transition from the exteriorsurface of the first wall section 12a to the exterior surface of thesecond wall section 12b. In the illustrated embodiment, contouredsurface 56 when viewed in cross-section, has a generally s-shape. Thecontoured surface 56 includes a non-tapered annular portion 57, anannular convex portion 58 and a concave annular portion 60. In oneparticular embodiment, the contoured annular surface 56 includes anon-tapered annular portion 57 which extends distally away from theengaging surface 54 and towards the end 8 a short distance, for exampleabout 0.010 inches, generally parallel to the inside surface of thesecond wall section and has an outer diameter substantially equal tothat of the first wall section 12a. This generally annular portion 57terminates in and is integral with the convex annular portion 58, havinga slope with a radius of about 0.115 inches. The convex portion 58connects and is integral with concave annular portion 60, having aconcave slope with a radius of about 0.300 inches. The concave annularportion 60 terminates in and connects with the outer portion 64 of thesecond wall section 12b having a different diameter, in this examplesmaller, than outer diameter of the first wall section 12a. As a result,the buttress 46 extends smoothly radially outward from the exteriorsurface of the second wall section to the exterior surface diameter ofthe first wall section, smoothing the transition between sections of thedevice having different outer diameters.

Wall section 12b surrounds that portion of internal compartment area 18that contains a means 25 for expanding and for occupying space incompartment 18 from delivery system 10. The thickness and the surfacearea of the second wall section 12b contribute to the rate of passage offluid through the membrane second wall section. In the preferredembodiment the second wall section or membrane cap 12b is about 1.442inches long, with an inner diameter of about 0.288 inches. The secondwall section 12b has an outer diameter of about 0.365 inches at thereceiving end 19 and about 0.378 inches at the portion not insertedwithin first wall section 12a. A membrane cap of substantially thesedimensions provides a desired fluid flow rate into the second wallsection of about 10-15 mg H₂ O/day and more particularly about 12-14 mgH₂ O/day. The two wall sections, sections 12a and 12b, at receivingmeans 19 and enclosing means 20 are close in size. There is clearance ortolerance in size to allow enclosing means 20 of wall section 12a asliding movement over the receiving means 19 of wall section 12b andprovide a small gap, preferably between 0.002-0.006 inches, between thewall sections so that a cyanoacrylate adhesive with good gap fillingcharacteristics will wick to form a bond between 19 and 20. In onepreferred embodiment, the outside diameter of the second wall section12b is about 0.362 inches, and the inside diameter of the first wallsection is about 0.365, providing a space of about 0.003 inches. Wallsection 12a and wall section 12b can be telescoped completely untilhalted by buttresses 44 or 46 into a closed and continuous internalwalled position. In the illustrated embodiment, optionally, a pluralityof longitudinal ribs 66 formed upon the outer surface of the second wallsection on the lead end or side of the engaging wall 54, space apart thefirst and second wall sections to define and form adhesive receivingcavities 68 between the first and second wall sections and in betweenthe longitudinal ridges. Optionally, the wall sections 12a and 12b canbe held together by heat fusion, by an adhesive, or the like. Preferablythe adhesive is a cyanoacrylate adhesive having a low-enough viscosityto wick into the joint and form a secure bond. A cyanoacrylate adhesivehaving the same qualities and characteristics as that sold by Permabondof National Starch and Chemical Company under the brand name PermabondUSP Grade 701 Adhesive is sufficient for the purposes of this invention.Buttresses 44 and 46 ensure that the juncture of 12a and 12b aresmoothly and precisely joined in mated contact without discontinuitieswhich would facilitate encapsulation of device 10.

Referring again to now to FIG. 1, there is shown, as discussed in moredetail with regards to FIG. 3, an embodiment of the mating end cap 38,adapting the end cap for ultrasonic welding to the first wall section12a; and maintaining the exit passageway 13 in contact with thebeneficial agent 7, while minimizing the dilution of the beneficialagent by adjacent body fluids present at the environment of use 41.

The end cap 38 is designed with specific features applicable to slowrelease implants osmotically driven being one specific type, thatrequired pressure drop for the operation of the implant. The cap isspecifically beneficial when delivering fluid sensitive materials andprotects the material to be delivered before and after activation of thedevice. The engineered exit port provides for a specific superficialformulation flow rate to eliminate dilution of the formulation byexternal fluids and maintains a required pressure drop for the operationof the implant. The engineered internal seal that provides point of usereadiness without having to reopen the device also provides for a longterm stability seal , protects formulation at start-up and has anengineered consistent rupture pressure for consistent startup. Designedheadspace and internal configuration minimizes internal pressure fromthermal expansion of formulations. An exit port maintains contact withthe formulation, through all phases of the pump operation. Ultrasonicweld for application of the cap that is designed for automatedapplication protection of formulations during the welding process, andgives a biocompatible joint seam as a result of a melt sink designedinto the weld configuration.

As best shown in FIG. 1, end cap 38 includes a first end cap side 70, asecond end cap side 72 and an exit passageway 13 extending from theexternal environment 41 into internal chamber 18. Exit passageway 13 isdesigned for an adequate formulation flow rate, driven by driving member25 and a partition member 27 including piston 29 to prevent dilution ofthe formulation in chamber 18 by the inflow of fluids from externalenvironment 41. Exit passageway 13 also maintains the pressure drop fora given rate of release of the formulation from device 10. Exitpassageway 13 is preferably designed so that the rate of outflow offormulation exceeds the rate at which fluids from the externalenvironment diffuse inwards.

Referring now to FIG. 2, exit passageway 13 further includes first side70 defining a first concentric exit aperture 74, in the preferredembodiment having a diameter of about 0.075 inches. Second side 72defines a second exit aperture 76, in the preferred embodiment having asecond diameter of about 0.017 inches. Concentric communicatingpassageway 78, having the same diameter as the second exit aperture,fluidly connects the first exit aperture 74 with the second exitaperture 76 over a distance of about 0.100 inches to provide a means forthe beneficial agent 7 to pass from the second side of the end cap tothe first side of the end cap and out to the external environment 41.The diameter of the exit passageway 76 determines the velocity of theefflux or outward flow of the beneficial agent 7 from the portion of theinternal compartment comprised of the first wall section 12a in thepreferred embodiment, a passageway diameter of 0.017 inches issufficient to generate a sufficient outward velocity of the beneficialagent therefrom. The length of the exit passageway provides a means forcompensating for slight variations in the efflux or outward flow rate ofthe beneficial agent. In one embodiment, a passageway length of 0.100inches was sufficient. First side 70 includes an external face 80, theexternal face generally defining a plane substantially perpendicular tothe longitudinal axis of the end cap 38. The communicating passageway 78has a generally frustro-conically shaped contoured interior annularsurface portion 79, smoothly joining the larger diametered first exitaperture 74 with smaller diametered communicating passageway 78 andsecond exit aperture 74. In one embodiment, the surface has a radius ofabout 0.028 inches, with a center 0.028 inches from the external face 80and 0.028 inches from the surface of the communicating passageway 78. 5Along its outer edge, the external face 80 joins with an annularconcentric rounded portion 82 for rounding off the edges of the device.In this particular embodiment, the annular rounded portion 82 is definedby a radius of about 0.066 inches, with a center about 0.066 inchesradially inward from the outermost edge 84 and about 0.066 inches inwardfrom the end face 80.

As best shown in FIG. 3, second side 72 of end cap 38 also includes amating portion 86 for engaging or mating with the first wall section12a, adapted for ultrasonic welding. The mating portion 86 includes anannular mating surface 88 on the second side 72 for engaging with thefirst wall section 12a, and a tenon 90 extending outward therefromtowards the first wall section 12a. In one particular embodiment, theannular tenon 90 has an annular thickness of about 0.018 inches, and isformed about 0.018 inches from the outermost edge 84 and extends outwardfrom the mating surface 88 to terminate in an apex 92. The tenon 90includes a first portion 94 that extends outward from the annular matingsurface 88 a distance of about 0.026 inches. Apex 92 includes a pair ofangular oblique faces 96 and 98 which are angled at about 28° from thevertical, i.e., a plane generally parallel to the longitudinal axis ofthe end cap 38.

As earlier described, first wall section 12a includes first open end 32.The open end 32 has an engaging surface portion 100 for engaging withthe end cap 38. This surface or open end 100 defines a mortise 102 forreceipt of the tenon 90 extending outward from the mating surface 88 ofthe end cap 38. In one particular embodiment, the mortise is defined bya first mortise wall 104, a second mortise wall 106 and a mortise bottomwall 108, the first and second walls 104 and 106 generally parallel tothe longitudinal axis of the first wall section 12a and spaced apartabout a distance of 0.030 inches. The mortise bottom surface 108connecting the first and second side walls 104 and 106 at a depth ofabout 0.026 inches from the engaging surface 100 of the first wallsection 12a.

Referring again to FIG. 1, it can be seen that end cap 38 is adaptedwith an inward extending portion 114 which defines a headspace 112between wall 12a and end cap 38, such that when the end cap is engagedwith wall 12a, defining chamber 18 which is filled with beneficial agentformulation 7, any resulting volume in chamber 18 which does not containformulation is confined to the headspace. In this way, regardless of theorientation of device 10, beneficial agent formulation is in contactwith seal 30 or with exit passageway 13 and entrance of fluid intochamber 18 from external environment 41 is inhibited.

As best shown in FIG. 4, second side 72 of end cap 38 also includes anextension 114 for sealing the exit passageway 13 and maintaining theexit passageway in contact with the beneficial agent 7 disposed within aportion of the internal chamber 18. The extension 114 includes agenerally cylindrical portion 116, extending outward and integral withthe annular mating portion 86 such that when the end cap 38 is matingwith the first wall section 12a, the annular cavity 112 is definedtherebetween to accumulate an air volume inserted or present in theinternal compartment 18 to allow for differential expansion ofbeneficial agent and plastic within the interior chamber 18. Theextension portion 114 at its terminal portion 118 includes an end capapex 120. Apex 120 includes or defines therein a depot 122 for receiptof a sealant. A sloping contoured surface 124 extends and connects theannular mating surface 86 with the depot 122. In one embodiment, thesloping surface 124 is generally s-shaped in cross-section and includesa first concave annular portion 126, a second concave annular portion128, and a convex annular portion 130 forming a generally s-shapedsurface in cross-section. In one preferred embodiment, the first concaveannular portion 126 has a slope generally defined by a radius of about0.029 inches from a center 0.125 inches radially outward from thecentral longitudinal axis and 0.083 inches along the centrallongitudinal axis from the apex 120 on second side 72. The secondconcave annular portion 128, integral with and extending radially inwardfrom the first concave annular portion 126, joins with the convexannular portion 130, and has a slope generally defined by a radius ofabout 0.125 inches from a center at 0.200 inches radially outward fromthe central longitudinal axis and 0.026 inches along the centrallongitudinal axis from the annular 120 on the second side 72. The convexapex portion 130 has a slope generally defined by a radius of about0.026 inches from a center 0.026 inches radially outward from thecentral longitudinal axis of the end cap 38 and the apex 120 on thesecond side 72. In addition FIG. 4 illustrates that after welding of theend cap 38 to the first wall section 12a, the outer surface of the tenon90 may be altered by the welding procedure to generally assume a shapesimilar to that of the mortise 102.

Depot 122 is comprised of the apex 120 defining a depot bore 132, forreceipt of the sealant 30, the depot bore in fluid communication withthe interior chamber 18 and the exit passageway 13. In the preferredembodiment, the depot bore 132 is defined by a generally cylindricalfirst or bore side interior surface 134 and a generally planar bottomsurface 136, the bore having a diameter of about 0.100 inches and adepth of about 0.050 inches. The bore side surface 134 slopes generallyinward towards the longitudinal axis of the end cap 38 as the surfaceextends from the end proximal to the second exit aperture 76 to the enddistant from the exit aperture at an oblique angle. In the preferredembodiment, the oblique angle is about 2° from the axis parallel to thecentral longitudinal axis of the end cap 38.

In the handling and operation of the device, the relationship betweenheadspace 112, depot 122 and exit passageway 13 plays a significantrole. Headspace 112 permits contraction and expansion of the formulation7 in device 10 during shipping and handling and also provides for thebuildup of pressure in device 10 after implantation into an animal.Headspace 112 insures that any air left in the formulation is not in theformulation where it can form a bubble adjacent to exit passageway 13but is confined to head space 112. If a bubble were permitted to formadjacent exit passageway 13, then when pressure built up sufficient toexpel the plug in depot 122, an inflow of fluid from the externalenvironment could dilute the formulation and the rate of delivery offormulation from device 10. In filling the device, heat treatment afterfilling assists in "setting" the formulation, locking the air bubbleinto place in headspace 12 where it will not affect initial operation ofdevice 10.

FIG. 6 illustrates in greater detail piston 29 of FIG. 1. Piston 29 isan elastomeric piston generally cylindrical in shape which incorporatesfirst and second deformable seals 140 and 142. Piston 29 provides a highinterference seal with minimum lateral force applied to the device wallwhich would impede longitudinal travel of the piston. The deformableseals 140 and 142 compensate for any irregularities in the internal wallof device 10 to provide an effective seal. The piston material, in onepreferred embodiment, can be formed of any of four grades of Santoprene®271 material, the most preferred grade being 271-55.

In one embodiment, the piston 29 includes a cylindrical body portion 145positioned within the first wall section 12a. The piston 29 includes thecylindrical first or central body member 145 with first and secondpiston ends 144 and 146 respectively. The deformable seals 140 or 142are formed at first and second piston ends 144 and 146 respectively. Inone particular embodiment, the deformable seals 140 and 142 include aflared, conical skirt member or section 148. As best shown in FIGS. 6and 7, the skirt 148 extends radially outward from the central bodymember 145 to terminate at a position spaced apart therefrom. Referringagain to FIG. 6, a metal location detection member 150 is formed withinthe central cylindrical body member 145. The skirt member 148, extendsradially outward a distance of about 0.016 inches from the respectivepiston end surface to extend longitudinally a distance of about 0.079inches at an oblique angle of about 15 degrees from the plane generallydefined by the surface of the central body member 145. As a result, thedistal ends of the piston 29 are biased radially outward whenarticulating within the inner diameter of the first wall section 12a.The thickness of the skirt enables the skirt to provide sufficientwiping pressure to the inside surface of the first wall section withoutinvoking such pressure as to cause the skirt to fold over.

Referring again to FIG. 5, first wall section 12a at its end distantfrom lead end 9 defines and forms an open end having a circumference forforming a lap joint 152 with wall section 12b. Second wall section 12bdefines rear end 8 and it surrounds that portion of internal compartment18 which initially contains an expandable driving means, hereillustrated by expandable driving members 25a-f. Second wall section 12bat its end distant from rear end 8 defines and forms an open end havinga circumference for forming lap joint 152. Second wall section 12b isadapted with buttress 56 for strength and precision of manufacture.Preferably the buttress is shaped to provide a smooth surface transitionbetween wall sections 12a and 12b to minimize irritation leading toencapsulation.

Lap joint 152 includes, in the illustrated embodiment, lap joints 152aand 152b, reciprocally received one within the other for matingengagement when the two edges are assembled together. The lap joints152a and 152b are of such a design as to provide a strong mechanicallyand hydrostatically intact seal when they are bonded together with anadhesive, such as a pressure-sensitive contact adhesive, amoisture-curing adhesive, an ultraviolet-curing adhesive or the like.While FIG. 1 shows the two wall sections assembled with the lap joint152a of first wall section 12a enclosing the outside of the lap joint152b of second wall section 12b, this arrangement is not critical andmay be reversed. However, the illustrated embodiment is preferred sinceit provides additional restraint on the second wall section or membranecup 12b pulling away from the lap joint. In addition, if the materialused in the formation of the wall section surrounding the osmoticdriving member, for example wall section 12b, is not as strong as thematerial used in the formation of the portion surrounding the beneficialagent 7, for example first wall section 12a, then the weaker material ispreferably positioned or disposed to the inside or inserted within thestronger material. For example, if cellulose acetate butyrate is usedfor the portion surrounding the osmotic driving member and polypropyleneis used to surround the beneficial agent 7, then the cellulose acetatebutyrate wall is preferably on the inside of the polypropylene wall.

In one embodiment of delivery device 10 as illustrated of FIG. 1, thesystem is manufactured as an implant comprising a body length of about8.7 cm, a diameter of the first wall section of about 10.5 mm, adiameter of the second wall section of about 9 to 10.5 mm, a beneficialagent 7 formulation occupying a length of about 45 mm, an initial totallength of about 26.54 mm, occupied by the expandable driving members,and an exit passageway of 2.5-2.6 mm in length and having a diameter of0.017 inches. This diameter has been found effective to restrict flow ofmaterials inwardly from the environment of use which the device is inuse. In a presently preferred embodiment, the exit passageway 13 anddepot 122 are occluded with a material such as wax that gets discharged,leaches or erodes when placed in the organic environment of use. Theimplant can be implanted into the peritoneal cavity using an implanter.

Generally, an implanter comprises a tubular member with a centrallongitudinal axial bore, a pointed, elongated, annular concavely beveledimplanting end and an implant-charging end. The implanting end and thecharging end communicate through a bore. A plunger adapted to beremovably inserted in the bore is designed for slidable movement thereinfor applying the necessary force for implanting the implant.Alternatively, the implant can be surgically or subcutaneously implantedin the peritoneal cavity.

Referring again to FIG. 1, first wall section 12a comprises acomposition that is substantially impermeable to the exchange of fluid,beneficial agent 7 and other ingredients contained in delivery system10. Wall section 12a, in a presently preferred manufacture, issubstantially impermeable to the ingress/loss of an external/internalfluid to serve as a means for substantially protecting a beneficialagent 7 that is sensitive to is exterior fluid present in theenvironment of use. Wall section 12a substantially restricts andprevents fluid from passing through wall 12a and entering intocompartment 18 in the region containing a beneficial agent formulation.In one particular embodiment, when used in conjunction with bovinegrowth factors, including bovine somatotropin, wall section 12a may beformed of a material which provides a reduced adherence of thebeneficial agent 7 to the wall 12a. For example, the use ofpolypropylene in the construction of wall 12a will reduce the adherenceof bovine somatotropin to the surface of wall 12a.

In the preferred embodiment, wall section 12a is formed of polypropylenebecause of its excellent low permeability to water and because of itslow surface tension which facilitates non-adhesion of beneficial agent 7to the internal surface as compared with other materials such aspolycarbonates, which empirically appeared to result in increasedbearding on the respective wall surface/beneficial agent interface,especially when the beneficial agent included bovine somatotropin.Preparing polypropylene for bonding preferably includes preparing thesurface thereof to increase the likelihood of an effective seal. Thoseskilled in the art will recognize that this may be performed by variousmethods, a non-inclusive list includes, for example, by priming with achemical primer, abrading or knurling the surface, treatment with plasmaand the like.

Second wall section 12b is permeable to the passage of fluid in at leasta portion and it is substantially impermeable to the passage of otheringredients contained in delivery system 10.

Wall sections 12a and 12b optionally comprise a plasticizer that impartsflexibility and workability to the wall. Wall 12, comprising sections12a and 12b, is nontoxic and, in a preferred embodiment, it maintainsits physical and chemical integrity; that is, wall 12 does not erodeduring the dispensing period.

Compartment 18 comprises a beneficial agent 7 formulation, whichbeneficial agent 7 formulation comprises a beneficial agent 7,identified by dots, and a pharmaceutically acceptable carrier 21,identified by wavy lines. The pharmaceutically acceptable carrier mayinclude more than one ingredient, such as a buffer 22, identified byhorizontal dashes; a pharmaceutically acceptable vehicle 23, identifiedby vertical lines; a pharmaceutically acceptable surfactant 24,identified by slanted lines; and other formulation ingredients, as areknown in the art.

Compartment 18 further comprises an expandable means or expandabledriving member 25 optionally comprising members 25a-f. Expandabledriving member 25 optionally comprises an osmagent homogeneously orheterogeneously blended with binder to form expandable driving member25.

Compartment 18 may optionally comprise a partition layer 27. Partitionlayer 27 may optionally include, as in this embodiment, a piston 29,discussed in more detail with respect to FIG. 5. The partition layer 27may include a portion which may be positioned between the drive piston29 and the expandable driving member 25. The partition layer maycomprise a composition that is substantially impermeable to the passageof fluid, and it further may act as a seal and restrict the passage offluid present in the expandable driving member into the beneficial agent7 formulation. Piston 29, alone or in cooperation with other portions ofthe partition layer 27, operate to essentially maintain the integrity ofthe beneficial agent 7 layer and the driving member layer 25. Portionsof the partition layer 27 acts also to insure that the expanding drivingforce generated by the expandable driving member 25 is applied directlyagainst piston 29 and thus is exerted on the formulation in compartment18.

In operation, as the expandable member 25 absorbs and imbibes fluidthrough fluid-permeable second wall section 12b from the environment ofuse, it expands and pushes against piston 29 causing piston 29 to slideinside compartment 18. The piston may be lubricated, for example, usinga silicone lubricant having the same characteristics as DOW 360 medicalfluid 1000 cs. Piston 29 moves towards exit passageway 13, driving thebeneficial agent 7 formulation in chamber 18 through passageway 13 fordelivering the beneficial agent 7 to the environment of use. Second wallsection 12b is telescopically capped by the engaging first wall section12a. The two sections can be joined together by adhesive bond or varioustechniques such as solvent weld, thermal weld, ultrasonic weld, spinweld, induction weld, mechanical lock or by similar welding or bondingoperations which may also be used in appropriate cases.

Delivery device 10 in FIG. 1 further comprises lead end 9, rear end 8,internal compartment 18, beneficial agent 7, pharmaceutically acceptablecarrier 21, pharmaceutically acceptable buffer 22, pharmaceuticallyacceptable vehicle 23, and a pharmaceutically acceptable surfactant 24.In addition, a salt such as NaCl or KCl may be present in amounts of1-4% by weight to assist stabilizing the state of formulation.

In a presently preferred embodiment, delivery device 10 comprises aplurality of expandable driving members 25a-f initially housed in secondwall section 12b. This configuration is merely illustrative and theremay be any number of driving member present. Generally, there are fromone to six expandable driving members; however, this number is notcontrolling. The expandable driving members in a presently preferredembodiment are formed as depots or layers and comprise like or unlikecompositions. For example, driving members 25a-f can be made as tabletscomprising like osmopolymers or like osmagents, or they can compriseunlike osmopolymers or unlike osmagents, or one or more of the memberscan be a composition comprising an osmopolymer together with anosmagent. The members can be the same or they can be different.

Referring again to FIG. 1, end cap 38 further comprises a depot 122 influid communication between internal chamber 18 and exit passageway 13.Depot 122 can receive a material which is discharged, leached or erodedaway during use. Preferably the material is wax or another materialwhich can be discharged and depot 122 is sized to provide for sufficientpressure to discharge the material through passageway 13. This materialserves several purposes: it seals delivery device 10 to preventpremature delivery of a beneficial agent 7 from delivery device 10 andto prevent evaporation of carrier components such as water duringstorage, it helps maintain the clean or optionally sterile environmentinside delivery device 10, and it protects the ingredients inside thedelivery device from oxidation by air and also protects the beneficialagent 7 from dilution by body fluids following implantation. Moreparticularly, the seal 30 consistently releases at the same pressureusing a 145 A wax in an end cap construction as described elsewhere inthis application. In one preferred embodiment, the seal 30 releases at apressure greater than 5-10 psi, more preferably greater than about 9psi.

First wall section 12a, which surrounds the internal space ofcompartment 18 initially occupied by the beneficial agent 7 formulation,comprises a composition that does not adversely affect the beneficialagent 7, the osmopolymer, the osmagent, other ingredients in device 10,the host, or the like. First wall section 12a comprises a compositioncomprising means that substantially limits or prevents the passage of anexternal fluid into device 10. The phrase, "substantially limits orprevents," as used herein, indicates the volume of external fluidpassing through first wall section 12a is substantially negligible, thatis, about zero up to about 1 μL per day (see example 2 discussed morefully elsewhere in this application). Typical compositions for formingfirst 10 section 12a are discussed in U.S. Pat. No. 5,057,318 forexample.

The second wall section 12b comprises a composition comprising meansthat aid in controlling fluid flux into the compartment area occupied bythe expandable driving member 25. The composition is semipermeable; thatis, it is permeable to the passage of external fluids such as water andbiological fluids and it is substantially impermeable to the passage ofbeneficial agents, osmopolymers, osmagents, and the like. Typicalcompositions comprising semipermeable materials for forming wall 12b areknown in the art, a non inclusive list includes the group consisting ofa cellulose ester, a cellulose ether and a cellulose ester-ether,including, for example, cellulose acetate butyrate. These cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucose unitfrom greater than 0 up to 3, inclusive. By "degree of substitution" or"D.S." is meant the average number of hydroxyl groups originally presenton the anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative fluid-permeablematerials are discussed in U.S. Pat. Nos. 4,874,388, 5,034,229, and5,057,318, for example. The amount of semipermeable materials presentlypreferred in wall 12b is from about 20% to 100%. In the presentlypreferred form, the wall is formed of polypropylene equivalent tomedical grade polypropylene PD626 sold by Himont, because of itsexcellent low water transport qualities and the relative low surfacetension relative to the beneficial agent 7 formulation as compared toother polycarbonates, especially when the beneficial agent is bovinesomatotropin.

Representative materials that can be used to regulate further the fluidflux of wall 12b include materials that decrease the fluid flux andmaterials that increase the fluid flux of wall 12b. Representativematerials optionally added to wall 12b for either decreasing orincreasing the flux are presented in U.S. Pat. Nos. 5,034,229 and5,135,523.

First wall section 12a and second wall section 12b optionally comprise anontoxic plasticizer. Representative plasticizers suitable for formingwall 12a or wall 12b are well known in the art and examples arepresented in U.S. Pat. Nos. 5,034,229 and 5,135,123.

Delivery device 10 in its compartment 18 can also comprisepharmaceutical carrier 21. Carrier 21 may optionally include viscositymodulating vehicles (23), buffers (22), surfactants (24), dyes, andother additives known in the art, examples of which are disclosed inU.S. Pat. Nos. 5,034,229 and 5,135,123 to comprise the beneficial agent7 formulation.

In a presently preferred embodiment, the beneficial agent 7 is bovinesomatotropin, in an amount of from about 25% to about 60% by weight (wt%) of the beneficial agent 7 formulation, preferably from about 30 wt %to about 45 wt %.

The expandable driving means 25 initially surrounded by second wallsection 12b and operable for pushing the beneficial agent 7 composition20 from delivery device 10 comprises, in a presently preferredembodiment, an osmopolymer. The osmopolymers interact with water andaqueous biological fluids and swell or expand to an equilibrium state.The osmopolymers exhibit the ability to swell in water and to retain asignificant portion of the imbibed and absorbed water within the polymerstructure. The expandable driving member 25 in another preferredembodiment comprises an osmagent. The osmagents are known also asosmotically effective solutes and they are also known as osmoticallyeffective compounds. The osmotically effective compounds that can beused for the purpose of this invention include inorganic and organiccompounds that exhibit an osmotic pressure gradient across asemipermeable, i.e. a fluid permeable, wall. The expandable drivingmember 25 yet in another preferred embodiment comprises an optionalosmagent dispersed within the osmopolymer. The osmagent or osmopolymercan comprise a tablet or a layer or can be pressed into second wallsection 12b. The osmagent or osmopolymer can be in any suitable formsuch as particles, crystals, pellets, granules, and the like, whenpressed into a tablet layer and into wall section 12b. Osmagents andosmopolymers are known to the art in U.S. Pat. Nos. 3,865,108,4,002,173, 4,207,893, 4,327,725, 4,612,008, 5,034,229, and 5,135,123 forexample.

Piston 29, positioned between the beneficial agent composition and theexpandable driving member 25, is a means for maintaining the separateidentity of the beneficial agent composition and the driving member, fortransmitting the force generated by the driving member against thebeneficial agent composition, and for substantially restricting thepassage of fluid between the beneficial agent composition and thedriving member.

End cap 38, illustrated in FIG. 1, provides a means for simply andconveniently assembling the device of the invention, and particularlyfor filling the device with internal components such as the drivingmembers, the partition and the beneficial agent formulation. The end cap38 is impermeable to fluid, providing protection for the fluid-sensitivebeneficial agent. Materials for forming end cap 38 may be chosen fromthose materials useful in preparing impermeable first wall section 12a.

The terms "exit means" and "exit passageway", as used herein, comprisemeans and methods suitable for the metered release of the beneficialagent 7 from compartment 18 of delivery device 10. This includesmaintaining sufficient efflux or outward velocity of the beneficialagent to prevent an inward flow of fluid from the external environmentto dilute the beneficial agent formulation in the portion of thecompartment comprised by the first wall section. The exit passageway 13includes at least one passageway, orifice, or the like, through firstwall section 12a for communicating with compartment 18. The expression"at least one passageway" includes aperture, orifice, bore, pore, porouselement through which the agent can migrate, hollow fiber, capillarytube, porous overlay, porous insert, and the like. The expression alsoincludes material that gets discharged, erodes or is leached from thewall in the fluid environment of use to produce at least one passagewayin delivery device 10. The expression includes structuralcharacteristics that concentrate stress at a precise point in the wallso that only a small amount of force will induce breakage in the wall,yielding a passageway through the wall from compartment 18 to theoutside of the device. A passageway or passageways can be formed by thedischarge, as a result of the pressure created by the expandable memberfor example, of a material such as a wax. The passageway can have anyshape such as round, triangular, square, elliptical, and the like, forassisting in the metered release of beneficial agent from deliverydevice 10. Delivery device 10 can be constructed with one or morepassageways in spaced-apart relations or more than a single surface of adosage form. Passageways and materials, equipment and methods forforming passageways are disclosed in U.S. Pat. No. 5,034,229.

Delivery device 10 can be manufactured by standard manufacturingtechniques. In one process, the first wall section 12a and the secondwall section 12b are independently injection molded or extruded into thedesired shape. Then, the first wall section 12a is filled with thebeneficial agent composition. The second wall section 12b is filled withan expandable driving member or members, and the piston 29 is next addedthereto in layered arrangement. Optionally, the piston 29 may be addedto the first wall section 12a after filling the wall section withbeneficial agent, in addition to, or instead of, the partition layeradded to second wall section 12b. Next, the two sections at their openends are slid together.

The delivery device of the present invention can be manufactured fordelivering numerous beneficial agents, including drugs, at a controlledrate to a presently preferred biological environment of use such aswarm-blooded animals, including humans; ruminants, such as bovines andsheep; porcines, such as hogs and swine; horses; and the like. Thedelivery devices provide for high loading of a beneficial agent and forits improved delivery in beneficially effective amounts (that is,amounts that provide a beneficial effect) over time. It is to beunderstood that the delivery devices can take a wide variety of shapes,sizes and forms adapted for delivering beneficial agents to environmentsof use. For example, the devices manufactured as delivery devices can beused for dispensing a beneficial agent in the anal-rectal passageway, inthe cervical canal, as an artificial gland, in the vagina, as asubcutaneous or intraperitoneal implant, and the like. The deliverydevices can be used in hospitals, nursing homes, outpatient clinics,sickrooms, veterinary clinics, farms, zoos, and other environments ofuse.

DETAILED DESCRIPTION OF EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

Example 1

A delivery device manufactured in the shape of an implantable deliverydevice according to the present invention is manufactured as follows.

An expandable driving member was prepared by first adding 10 liters ofwater and 526 g of polyvinylpyrrolidone to a stainless steel containerand mixing the components for 1 hr to obtain a smooth binder solution.Next, approximately 20 kg of sodium chloride was milled in a mill to anumber 21 size mesh screen. Then, 17.5 kg of the milled sodium chlorideand 7.5 kg of sodium Carbomer®, a sodium salt of a polyacrylic polymer,were transferred to the granulator bowl of a fluid bed granulator and2.46 kg of binder solution was slowly sprayed onto the materials in thegranulator. Granules were formed in this manner. Next, the granulatedmaterial was sized by forcing it through a 0.0469 in mesh is screen in ascreen separator. Then, the granulation was divided into two 12.8 kgsub-batches. For each sub-batch, 130 g of magnesium stearate was addedand the ingredients were blended for 3 min at 9 rpm to produce ahomogeneous expandable driving composition. The composition next waspressed into osmotically active tablets in a tablet press at a pressureof 2,000 lbs to produce a round, flat-faced 266 mg tablet as anexpandable driving member .

The semipermeable wall (membrane cup) that surrounds a compartment forcontaining the osmotically active tablets was prepared as follows.First, 1.0 kg of tributyl citrate and 9.0 kg of cellulose acetatebutyrate were dry mixed in a mixer for 30 min. This produced apolymer/plasticizer blend of 90/10 ratio for the rate-controllingsemi-permeable second wall section 12b. The blend was then injectionmolded into a semi-permeable membrane cup of the desired shape with anopen end for receiving an expandable driving member and for mating withthe forward wall section, whose preparation is as follows.

The impermeable first wall section 12a of the delivery device 10 whichforms the compartment holding the beneficial agent 7, is prepared byblending the polypropylene (Himont PD626) with a blue colorant (0.1% FD& C blue lake). The mixture is then injection molded into the first orforward impermeable wall section 12a in the desired shape, with the opensecond end 34 for mating with the semi-permeable second wall section ormembrane cup 12b and an open forward or lead end 32 for the end cap 38 .That portion of the first wall section 12a which mates with thesemi-permeable second wall section or membrane cup 12b is molded with adiamond shaped pattern over a portion of its surface to enhance theadhesive bond between it and the membrane cup. Surface preparationensures satisfactory adhesive bonding of polypropylene to othermaterials. In the case of the first wall section 12a, in addition to themechanical configuration described above, this may be accomplished byeither applying a primer to the glue-joint area or by treating thesurface with a plasma made from a mixture of oxygen andtetrafluromethane gases prior to applying the adhesive. That matingportion of the first or forward wall section which mates with the endcap 38 is molded with circumferential, rectangular-shaped mortise 102 tofacilitate ultrasonically welding the end cap 38 to the forward wallsection 12a as described more fully elsewhere in this application.

The end cap 38 was prepared by blending polypropylene (Himont PD626)with a blue or white colorant (0.1% FD & C blue lake or 1.0% titaniumdioxide, respectively). This mixture is then injection molded to formthe end cap 38, as described more fully earlier in this application,having the exit aperture with a 0.017 inch diameter approximately 0.1inches long, an internal cavity for containing a wax sealant material,and a precisely determined circumferential configuration around theouter perimeter of the end cap 38 to facilitate ultrasonic welding ofthe cap to the forward wall section 12a. This configuration includes awedge shaped energy director with an included angle of 56°, which isbeneficial to achieving a high quality ultrasonic weld with crystalline,polymeric materials being joined. The internal cavity is filled withmolten wax (Witco 145), which solidifies to form a seal to the orificeport.

The piston 29 is prepared by insert injection molding Monsanto brandthermoplastic elastomer sold under the brand name "Santoprene® 271-55",into the piston with a circumferential, cantilevered lip at each end anda metal detection core in its center. The metal core is cylindrical inshape with a flat face at each end and is manufactured in a separateprocess by sintering at 1300° F. a metal alloy consisting of nickel andiron in a 50/50 ratio. The metal core is inserted into the mold when itis in the open position, and the thermoplastic elastomer is injectedaround it during the injection molding process. The piston 29 thusformed is lubricated with silicone medical fluid to facilitate movementof the piston inside the device during assembly and operation and tominimize piston set during storage.

The delivery device 10 is partially assembled by first charging thesecond wall section or semi-permeable membrane cup 12b with six of theosmotic tablets 25a-f. The second wall section 12b is then partiallyinserted into the impermeable first or forward wall section 12a of thedevice 10 and two drops of moisture-cured cyanoacrylate adhesive aredropped onto the exposed portion of the joint between the first andsecond wall sections, where the adhesive is drawn into the remainder ofthe joint by capillary action. The first and second wall sections 12 and12b are then fully inserted to form a mechanically strong, water-tightseal. The lubricated piston 29 is then inserted through the remainingopen end 32 of the first or forward wall section 12a, using a tool whichallows air to pass by the piston 29 as it is moved into position againstthe osmotic tablets 25a-f and insert the piston within the wall sectionwithout having the skirt member rolled. The tool used is a thin-walledfunnel open at both ends having an internal chamber for receipt of thepiston therein.

Next, the delivery device subassembly, comprised of the second wallsection or membrane cup 12b, the osmotic tablets 25a-f, the impermeablefirst or forward wall section 12a and the piston 29, is filled with 2250mg of the beneficial agent 7 formulation at 35° C. The formulation iscomprised of 36.5%±1.5% Zn-bST in a phosphate buffer, glycerols, wettingagent, salt excipient blend where the w/w/w/w proportions of phosphatebuffer, glycerol, Tween-80, and KCl are 48.38/48.38/0.24/3.0respectively. The phosphate buffer is 60:40 monobasic:dibasic sodiumphosphate, and the molarity is 0.45. Then, a waxed end cap 38 is placeinto position on the open lead end 9 of the first wall section 12a byultrasonic welding. The filled implant 10 is heat treated after beingplaced into a sterile package, for example, by heating the about 40° C.for about 16 hours.

Example 2

The pistons according to the invention were tested as follows:

A formulation of ZnbST in a phosphate/glycerol/Tween/NaCl excipient wasprepared using titrated water (³ H₂ O). The specific activity of thelabelled water was 1.0 mCi/ml, and should be sufficient to provide adetection limit of 1 μgm of water. The formulation was loaded into 10 mmosmotic implants with two different piston designs (1.0× and 1.5×), anda third group that had the compartment surrounding the osmotic drivingmember prehydrated.

                  TABLE 1                                                         ______________________________________                                        Pump configurations                                                           Group         Piston  Pre-hydration                                           ______________________________________                                        1             1.0x    no                                                      2             1.5x    no                                                      3             1.0x    yes                                                     ______________________________________                                    

The implants were sampled in duplicate for group 1, and triplicate forgroups 2 and 3, at intervals of 0, 3, 6, 12 and 18 weeks. Formeasurement of total water transport to the osmotic driving members,e.g. salt tablets, of the internal chamber 18 surrounded by thesemi-permeable wall section 12b, the second wall section 12b wasseparated from the first wall section 12a and the end cut off. Salttablets were expelled and dissolved in water. An aliquot of the solutionwas added to the liquid scintilallation cocktail and counted by standardliquid scintillation counting techniques. Table 2 lists the individualmeasurements of the total water content.

                  TABLE 2                                                         ______________________________________                                        TRANSPORT OF WATER FROM THE                                                   FORMULATION COMPARTMENT TO THE                                                ENGINE COMPARTMENT DURING STORAGE AT 4 C.                                     Group/                                                                        Replicate                                                                             Week 0  Week 3   Week 6                                                                              Week 12 Week 18                                ______________________________________                                        1/1     12      37       75    7413*                                          130                                                                           1/2     12      50       68    98                                             148                                                                           1/3     --      --       --    --                                             162                                                                           2/1     460*    43       66    331*     515*                                  2/2     14      41       67    97      150                                    2/3     1209*   45       235*  102     146                                    3/1      4      56       82    114     189                                    3/2     101*    46       65    711*     230*                                  3/3      5      51       76    112     139                                    ______________________________________                                         *possible statistical outlier (greater than 3 standard deviations from        mean excluding theses points).                                           

FIG. 8 is a graph depicting the relationship between 1 μgms of H₂ Oby-passing the piston versus time (weeks).

FIG. 9 is a graph showing μgms of H₂ O by-passing the piston versus timeexcluding outliers.

A variable amount of water (0.1-7 mg) transferred from the portion ofthe internal compartment 18 surrounded by the first wall section 12a tothe portion surrounded by the second wall section 12b during the fillingprocedure for approximately 25% of the implants 10. There was a highpump to pump variability at all time points, on top of a small increasedue to subsequent water transport from the internal compartmentsurrounded by the first wall section 12a to the salt tablets. The linearregression estimates of the rate of water transport along with 95%confidence intervals were as follows:

All data included: 20.0±8.9 μgms/week

excluding outliers: 7.1±0.1 μg/week

Thus, the worst case estimate (upper 95% confidence interval with alldata included) was 28.9 μgms per week, or approximately 1.5 milligramsper year. The best case estimate (lower confidence interval excludingoutliers) was 7.0 μgms per week, or 0.36 milligrams per year. Thereforeit was concluded, assuming the acceptable limit set by the amount ofwater that can be lost from the formulation without exceeding a 1%increase in protein assay, is approximately 60 milligrams, that thepiston tested in these experiments was deemed adequate to maintainseparation between the portion the internal compartment 18 surrounded bythe first wall section 12a and the portion of the internal compartment18 surrounded by the semipermeable second wall section 12b for theanticipated shelf life of five years or more, i.e., "substantiallylimits or prevents" the passage of fluid around the piston.

Example 3

Delivery devices according to the present invention were tested in vivoas follows.

Example 3a (11466)--Weekly Subcutaneously Administered Pellets

A study was undertaken to determine the effect of 40 or 80 mg A-25 bSTpellets administered subcutaneously weekly during a 84-day beef cattlestudy on 1) growth, 2) feed efficiency and 3) carcass composition.

One hundred eighty Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were used. Stocking density was 5 animals per pen. Thetrial consisted of 180 steers with replicates of 12 pens (60 animals)per treatment group (control, 40 mg bST/wk, and 80 mg bST/wk). The studylasted 84 days (12 weeks) exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein("P"). Potable water was available ad libitum. Pens were randomlydistributed among treatments:

                  TABLE 3                                                         ______________________________________                                        Treatment                                                                     Trial   Group   Pens      Animals                                                                             Description                                   ______________________________________                                        1       1       12        60    Control                                       1       2       12        60    40 mg/wk A-bST                                                                Pellets                                       1       3       12        60    80 mg/wk A-bST                                                                Pellets                                       ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownon the following Table:

                  TABLE 4                                                         ______________________________________                                        TREATMENT                                                                                            40 mg/wk   80 mg/wk                                    Parameters    Control  bST Pellets                                                                              bST Pellets                                 ______________________________________                                        Initial Body Wt (kg)                                                                        390.3    390.3      390.3                                       Final Body Wt (kg)                                                                           499.5a   495.0a     510.4b                                     Carcass Wt. (kg)                                                                            308.3    304.3      312.2                                       Dressing Percent                                                                             61.7     61.5       61.2                                       Carcass Gain Response                                                                       --       No Gain    39%                                         Non-Carcass   --       No Gain    61%                                         Gain Response                                                                 ______________________________________                                         a, b  different superscripts indicate that numbers in a row are               significantly different (p < .05)                                        

It was observed that neither dressing percentage nor carcass weight weresignificantly increased. Further, at a higher dosage, most of theincrease in body weight due to bST treatment was allocated to thenon-carcass components.

Example 3b--Weekly Subcutaneous or Intraperitoneal Pellets

A study was undertaken to determine whether the effect of 80 mg A-bSTpellets during an 84-day beef cattle study was comparable whenadministered subcutaneously and intraperitoneally.

Two hundred seventy Angus X Hereford beef steers weighing approximately350 kg (770 lbs) were bought and divided into three study groups.Stocking density was 5 animals per pen. Each study group consisted ofreplicates of 6 pens (30 animals) per treatment group (control, 40mgbST/wk subcutaneous pellet, and 80 mgbST/wk intraperitoneal pellet).The study lasted 84 days exclusive of the pretreatment period. The dietfor all animals, on a dry matter basis, contained 16% crude protein.Potable water was available ad libitum. Pens were randomly distributedamong the treatments:

                  TABLE 5                                                         ______________________________________                                        Trial Treatment Pens    Animals                                                                              Description                                    ______________________________________                                        2     1         12      60     Control                                        2     2         12      60     80 mg/wk A-bST                                                                Subcutaneous (SQ)                                                             Pellet                                         2     3         12      60     80 mg/wk A-bST                                                                Intraperitoneal (IP) Pellet                    3     1         12      60     Control                                        3     2         12      60     80 mg/Wk bST SQ                                                               Pellet                                         3     3         12      60     80 mg/wk bST IP                                                               Pellet                                         4     1         12      60     Control                                        4     2         12      60     80 mg/wk A-bST SQ                                                             Pellet                                         4     3         12      60     80 mg/wk A-bST IP                                                             Pellet                                         ______________________________________                                    

The animals were slaughtered for carcass analysis. The results are shownin the following Tables:

                  TABLE 6                                                         ______________________________________                                        TREATMENT                                                                                           80 mg/wk SQ 80 mg/wk IP                                 Parameters   Control  bST Pellets bST Pellets                                 ______________________________________                                        Carcass Wt. (kg)                                                                           395.1    395.0       397.7                                       Final Body Wt (kg)                                                                          493.7a  499.5a      507.8a                                      Carcass Wt. (kg)                                                                           304.2    304.2a      311.2a                                      Dressing Percent (%)                                                                        61.6a    60.8b       61.2ab                                     Carcass Gain (%)                                                                           --        0%         61%                                         Response                                                                      Non-Carcass (%)                                                                            --       100%        39%                                         Gain Response                                                                 ______________________________________                                         a, b  different letters indicate that numbers in a row significantly          different (p < .05)                                                      

It can be seen that, while the dressing percentage ofsubcutaneously-treated cattle was significantly decreased relative tothe control, the dressing percentage of intraperitoneally-treated wasnot significantly changed relative to the control.

Example 3b--Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellets

A study was undertaken to determine whether the effects ofintraperitoneal release of bST, of estrogen pellets, or of the combinedeffects of the two.

Two hundred fifty-six cross-bred large frame steers weighingapproximately 430 kg (948 lb) were assigned to a control group and threetreatment groups and implanted with intraperitoneal bST pumps or/aridestrogen pellets. The bST formulation used was a 35% A bST load in aphosphate buffer, glycerol, Tween-80 and KCl excipient. The w/w/w %proportions respectively were 48.38148.38/0.24/0%. The phosphate bufferwas 60:40 monobasic:dibasic sodium phosphate at 1.0 M. The time ofrelease of both bST and estrogen was 87 days prior to slaughter. Theresults are shown in the following Table.

                  TABLE 7                                                         ______________________________________                                        TREATMENT                                                                                                         12 mg/d                                                   12 mg/d bST 0                                                                            0 bST/200 ug/d                                                                         bST//200 ug/d                             Parameters                                                                            Control Estrogen   Estrogen Estrogen                                  ______________________________________                                        Initial 430.3   430.3      430.3    430.3                                     Body Wt                                                                       (kg)                                                                          Final Body                                                                            544.9a  552.2b     567.1c   576.4d                                    Wt (kg)                                                                       Carcass Wt                                                                            334.2a  340.3b     349.3c   359.7d                                    (kg)                                                                          Dressing                                                                               61.3a   61.6a      61.6a    62.4b                                    Percent                                                                       (%)                                                                           Carcass N/A     84%        68%      112%                                      Gain                                                                          Response                                                                      Non     N/A     16%        32%      -12%                                      Carcass                                                                       Gain                                                                          Response                                                                      ______________________________________                                         a,b different superscripts indicate that number in a row are significantl     different (P < .05)                                                      

These results indicated that a significant improvement in dressingpercentage and carcass weight were achieved by intraperitoneal osmoticpump release of bST concurrent with estrogen treatment.

Example 3c--Combination of Intraperitoneal bST Osmotic Pump and EstrogenPellet

A study was undertaken to determine performance of intraperitonealosmotic pumps in finishing cattle concurrently being administeredestrogen. Six hundred seventy-two cross-bred large frame cattle weighingapproximately 412 kg were bought and assigned to a control group and sixtreatment groups of 96 cattle each. The cattle were implanted withintraperitoneal osmotic pumps capable of delivering 6, 12, 15 or 18 mgbST per day during an 84-day period ending with slaughter. The cattlereceived estrogen pellets during a 126-day period ending with slaughter.The estrogen release is estimated at about 200 ug/d. The results areshown in the following table.

                                      TABLE 8                                     __________________________________________________________________________    TREATMENT                                                                     load      30%     40% 45%                                                     Parameters                                                                          Control                                                                           6 mg/d                                                                            12 mg/d                                                                           15 mg/d                                                                           6 mg/d                                                                            12 mg/d                                                                           18 μg/d                                      __________________________________________________________________________    Initial                                                                             411.9                                                                             411.9                                                                             411.9                                                                             411.9                                                                             411.9                                                                             411.9                                                                             411.9                                           Body Wt                                                                       (kg)                                                                          Final Body                                                                          555.1a                                                                            565.6bc                                                                           568.7bc                                                                           569.6c                                                                            561.8b                                                                            563.5bc                                                                           566.5bc                                         Wt (kg)                                                                       Carcass Wt                                                                          343.0a                                                                            353.1bc                                                                           357.2d                                                                            355.4cd                                                                           350.8b                                                                            351.3b                                                                            353.8bcd                                        (kg)                                                                          Dressing                                                                             61.8a                                                                            62.4b                                                                             62.8b                                                                             62.4b                                                                              62.4b                                                                            62.4b                                                                             62.5b                                           Percent                                                                       Carcass                                                                             --  96% 104%                                                                              86% 116%                                                                              99% 95%                                             Response                                                                      Non-  --   4%  -9%                                                                              14% -16%                                                                               1%  5%                                             Carcass                                                                       Response                                                                      __________________________________________________________________________

The results confirm that concurrent intraperitoneal treatment offinishing beef cattle with bST and estradiol significantly increasedressing percentage and carcass weight and furthermore allocated most ofthe increased weight to the carcass components.

Example 4

FIG. 10 is a graph depicting the real time pressure release for a sealof Multiwax X-145a wax having a thickness of 0.050 inches. The pressureat which the seals blew was between 6 and 9 psi from exit passageway ofhaving a 0.017 diameter and a length of 0.100 inches.

Thus, an exit passage having a 0.017 inch diameter and a length of 0.100inches, in fluid contact or abutted by a seal of 0.050 thick, wouldburst the seal between about 6-9 psi.

Example 5

FIG. 11 is a graph showing the effect of the exit port aperture diameteron the diffusion of water using an exit passageway length of 0.100inches and specified diameter. Empirical observations of the respectivedevices indicate that the beneficial agent formulation turned white inall devices with 0.050 inch diameter outlets with small pockets of waterentrained in the formulation. The beneficial agent formulation was clearin all devices having an exit port aperature of about 0.017 inches indiameter.

Thus an exit aperature having a diameter of 0.017 inches providessufficient outward velocity or efflux of the beneficial agent from thecompartment defined by the first wall section, i.e., "substantiallylimits or prevents" diffusion of fluid back into the internalcompartment defined by the first wall section.

The novel devices of this invention use means for the obtainment ofprecise release rates in a fluid environment of use while simultaneouslymaintaining the integrity of the device and the stability of thefluid-sensitive beneficial agent 7 within the device. While there hasbeen described and pointed out features of the invention as applied topresently preferred embodiments, those skilled in the art willappreciate that various modifications, changes, additions and omissionsin the devices illustrated and described can be made without departingfrom the spirit of the invention.

What is claimed is:
 1. An improved delivery device for storing andprotecting a beneficial agent formulation and for dispensing thebeneficial agent formulation to an animal, the delivery devicecomprising:a) a housing comprising a fluid impermeable portion and afluid permeable portion, the portions forming an internal compartment;b) a beneficial agent formulation in the internal compartment; c)expandable means in the compartment for pushing the beneficial agentformulation from the delivery device; and e) exit means for deliveringthe beneficial agent formulation from the internal compartment to theanimal over a prolonged period of time, wherein the improvementcomprises headspace formed in a part of the portion of the internalcompartment which contains the beneficial agent formulation whichheadspace is located away from the exit means and which head spaceserves to accumulate an air volume in a part of the portion of theinternal compartment which contains the beneficial agent formulationaway from the exit means.
 2. A delivery device according to claim 1wherein the housing includes an end cap, the end cap comprising aninwardly extending portion, the inwardly extending portion and defininga space therebetween.
 3. A delivery device according to claim 2, furtherincluding means for maintaining a seal between the exterior environmentand the interior chamber until the osmotic pressure within the devicereaches a predetermined pressure of between greater than 5 and 10 psi.4. A delivery device according to claim 2, wherein the end cap includesmating means for adapting the end cap to ultrasonic welding to the, themating means positioned where the end cap and the fluid impermeableportion join.
 5. A delivery device as set forth in claim 4, wherein endcap further comprises a first side and a second side, and wherein themating means includes a tenon extending outwards from the second side ofthe end cap, the fluid impermeable portion defining a mortise therein,the tenon sized and positioned for receipt within the mortise.
 6. Adelivery device for storing and protecting a beneficial agentformulation and for minimizing the dilution of the beneficial agentformulation during the dispensing of the beneficial agent to an animal,the delivery device comprising:a) a housing comprising a first wallsection and a second wall section assembled together to form an internalcompartment, wherein the first wall section is substantially impermeableto the passage of fluid, wherein the second wall section is permeable inat least a portion, to a predetermined rate of fluid from the externalenvironment into the internal compartment comprised by the second wallsection; b) a beneficial agent formulation in a portion of the internalcompartment comprised by the first wall section; c) expandable means ina portion of the compartment comprised by the second wall section forpushing the beneficial agent formulation from the delivery device; andd) an exit passageway through the first wall section, the exitpassageway comprising a seal wherein said seal is discharged, leaches orerodes to become unsealed when the pressure within the compartmentreaches a predetermined level and which seal thereafter remains unsealedto allow continuous release of beneficial agent during the entire timeof delivery, and the exit passageway having a length and area whichmaintains sufficient outflow of the beneficial agent formulation toprevent an inward flow of fluid from the external environment.
 7. Adelivery device according to claim 6, the wherein the beneficial agentis bovine somatotrophin and the predetermined rate of fluid from theexternal environment is about 10 to about 15 mg/water per day.
 8. Adelivery device according to claim 7, wherein the predetermined rate offluid is attained by a selected thickness of the second wall section, aselected surface area of the second wall section, and second wallsection comprising a selected material.
 9. A device according to claim6, wherein the exit passageway further includes the first wall sectiondefining a passageway of a predetermined inner diameter sufficient togenerate a sufficient outward velocity of the beneficial agentformulation to prevent an inward flow of fluid from the externalenvironment to dilute the beneficial agent in the portion of thecompartment comprised by the first wall section.
 10. A device accordingto claim 9 wherein the exit passageway further includes means forcompensating for slight variations in the outward flow rate.
 11. Adevice according to claim 10 wherein the means for compensating forslight variations in the outward flow rate includes adjusting thethickness of the first wall section defining the exit passagewaytherein.